Memory immune responses provide enhanced protection from pathogens previously encountered, and are remarkably long-lived, persisting over a lifetime of an individual. The ability of the immune system to generate memory is the basis for the success of many vaccines in preventing or eradicating deadly diseases; however, generation of immune memory that protects against infectious agents such as HIV, malaria and many bacterial pathogens has remained elusive. Memory immune responses begin with recognition of an antigen by naive T cells via their cell surface T cell antigen receptor (TCR) resulting in proliferation and differentiation to activated effector cells producing cytokines to recruit and activate immune cells from antigen clearance. Most of these activated effector cells die, but a small proportion of activated and/or effector T cells persists as memory T cells that mediate an enhanced recall response for rapid antigen clearance. Aside from this general scheme, the mechanisms by which immune memory is generated, how it mediates superior immune reactions, and how it is maintained in the host are largely unknown. We have taken a biochemical approach to dissect the signal transduction pathways mediated through the TCR in naive, effector and memory CD4 T cells to understand the mechanisms controlling their diverse functions, lifespans, and activation properties. We found that while naive T cells exhibit TCR- coupled signaling similar to T cell lines and clones, effector T cells are marked by a striking amplification of signals and alteration of the proximal TCR signaling complex, and memory CD4 T cells exhibit a profound dampening of signaling, with a remarkable decrease in expression of the critical linker/adapter molecule SLP-76. These results suggest the hypothesis that TCR-mediated signaling changes drive T cell differentiation to effector and memory subsets. It is the goal of this proposal to directly test this hypothesis and elucidate the precise roles of specific signaling changes on effector and memory T cell differentiation and function in vitro and in vivo, using biochemical, molecular and cellular immunological approaches. The proposed research has the potential to elucidate precise mechanisms for regulation of memory immune responses on the biochemical level and identify novel targets for manipulation of memory and effector immune responses in anti-pathogen immune responses and in autoimmune diseases.